Abstract CD46 is a human-specific immunoregulatory protein with signaling and receptor properties in immune cells. Activation of CD46 can lead to a variety of outcomes, ranging from immune regulation to inflammation, depending on the relative levels of the two isoforms. Several viruses and bacteria target CD46 during infection, using it as a receptor or downregulating it in infected cells. N. gonorrhoeae (Ng) interacts with epithelial cell CD46 at multiple levels. Infection via the Type IV pilus directly or indirectly triggers its phosphorylation, alters its trafficking, and causes its secretion. Although is published on the numerous biological phenotypes associated with CD46, little is known about the molecular mechanisms underlying them. We have obtained compelling evidence that the pathogenic Neisseria, N. gonorrhoeae and N. meningitidis, stimulate CD46 processing by Presenilin/[unreadable]-Secretase (PS), a protease complex that regulates many important signaling proteins. Our goal is to understand how Presenilin/[unreadable]-Secretase processing of CD46 affects its signaling activities of host cells, and how these activities relate to infection. We propose a model for this CD46 processing pathway and we propose to test the predictions from this model. We are uniquely positioned for these studies with our tail-specific mAbs and the Presenilin double negative mutant cell line. Our studies will shed light on the host aspect of Neisseria biology. Our findings will also add to the knowledge base of CD46 function, and hopefully shed light on other pathogens/CD46 interactions.